In collaboration with, and in support of ongoing activities undertaken in Dr. David Ho’s lab, my research aims are focused on the development of effective strategies with the potential to prevent HIV-1 infection, or assist in controlling or curing HIV disease. Our research strategies are mainly focusing on these two areas:

Engineering multi-specific antibodies. Previously, we reported a mechanism-based strategy to construct a series of HIV-1 receptor or co-receptor anchoring-based bispecific Abs that were capable of simultaneously attacking two critical sites involved in HIV entry. We engineered over 200 bispecific antibodies and systematically evaluated their antiviral activity and developability potential in vitro, and used these data to downselect a lead bispecific antibody for in vivo efficacy studies in humanized mice. These efforts led to the identification of 10E8.4/iMab, a bispecific antibody candidate that has not only exquisite antiviral breadth and potency, but also favourable product development potential (for example, high solubility and low aggregation potential). A GMP cell clone expressing 10E8.4/iMab has been created, and the GMP manufacture of 10E8.4/iMab will begin shortly. 10E8.4/iMab has been engineered to have no Fc-mediated effector function because it has one arm targeting a host-cell protein (CD4). Its sole anti-HIV effect is to block HIV entry, and subsequently the next round of infection by virions, which may be sufficient for its application as an HIV prevention agent. However, 10E8.4/iMab has not demonstrated an ability to induce the killing of activated latent reservoir cells, which would be beneficial in an HIV treatment setting. With this in mind, we recently expanded our antibody engineering efforts to generate a new panel of bispecific and trispecific antibodies that target different epitopes on the Env protein. We hypothesize that these new multi-specific antibodies could address the limitations of traditional monoclonal antibodies by providing a higher genetic barrier and potentially also benefiting from valiancy contributions. In addition to limiting escape mutant virions from arising, these multi-specific antibodies are also optimized for the killing of Env-expressing cells. The best performing antibody constructs identified by virus neutralization activity and HIV-1 infected-cell binding and killing will then be evaluated in animal models for their cell-killing capacity, ability to restrict or eliminate latent reservoir cells after activation, and ability to prevent or limit the establishment of the HIV-1 latent reservoir. Using such an approach, we hope to offer to the field one or two multi-specific antibodies that could be applied toward the elimination of latent reservoir cells as one critical component of a multi-pronged approach to HIV-1 eradication.

Engineering bispecific based antibody-drug conjugates. Currently available antiretroviral therapies (ART) can reduce the level of HIV in the blood to an undetectable level, but they cannot eliminate the latent reservoir, thereby imposing a major obstacle to curing HIV-1 infection. A number of latency reversal agents (LRAs) has shown activity in vitro, but all have little or no impact on the latent reservoir in clinical trials to date. Because increasing the doses of LRAs is prohibitive in their current forms due to the potential for increased systemic toxicity, alternative strategies for the specific targeting and activation of the latent HIV reservoir are needed. We hypothesize that targeted delivery of LRAs to HIV reservoir cells could markedly increase the therapeutic index of LRAs by several orders of magnitude. We proposed to harness the exquisite specificity of bispecific antibodies for targeting the HIV latent reservoir. We will then conjugate a panel of LRAs to each of the promising bispecific antibodies to deliver such agents preferentially to latently infected cells while minimizing their potential LRA delivery to off-target cells. We are currently engineering a panel of bispecific ADCs capable of targeting the narrow subsets of CD4+ resting memory T cells that have been characterized as the likely HIV reservoir cells in blood and tissues. Our preliminary results suggested that the dual targeting/activation strategy is feasible. We will continue to take an iterative approach to assess bispecific ADC binding affinity and avidity, selectivity of LRA delivery, and HIV activation from the latent reservoir in vitro or ex vivo. The ADCs with the most promising in vitro or ex vivo properties will be further evaluated for their impact on the latent reservoir in vivo using a humanized mouse model of HIV infection and treatment.

The goal of our research is to develop new forms of protective antibodies for HIV prevention and eradication. Using antibody engineering technologies, we focus on generating a novel modified antibody-like molecule that has the ability to specifically target and eliminate HIV infected cells, thereby potentially eradicating HIV infection.

NAME: Yaoxing Huang

TITLE: Associate Professor/Staff Investigator

EDUCATION

1988

B.Med. Shanghai Medical University, China

1997

Ph.D. New York University, NY

RESEARCH EXPERIENCE

1992-1997

Teaching and Research Assistant Department of Microbiology, NYU School of Medicine, New York Aaron Diamond AIDS Research Center (ADARC), New York